Our overall program is interested in the fundamental issues regarding the evolution of polyketide natural products. The focus of these studies is from two complementary perspectives. The first deals with specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. The second perspective focuses on structurally related polyketides and the co-evolution of their protein targets. Polyketide natural products are ideal subjects for these studies due to their complex structure and diverse biological activities which have shown utility towards the study and treatment of a number of therapeutic areas. During the previous research period we have shown that conformation is an important complement to classic structure-activity relationships and provides useful information for the development of future chemotherapeutic agents. As a proof of principle, a conformation-activity relationship study of the microtubule-stabilizing natural products, the epothilones, provided important information with regards to the pharmacophore as well as new leads for further development. During the next grant period, our studies will investigate three fundamentally unique projects, 1. Conformation-activity relationships of peloruside A, 2. a study of the evolutionary relationship between apoptolidin and structurally related plecomacrolides, bafilomycin and concanamycin, and 3. The development of precursor-directed biosynthetic techniques for the preparation of complex polyketide analogues. The complex natural products targeted in this application will be prepared via unique but practical synthetic strategies. Moreover, where appropriate, we have incorporated the development of a number of new synthetic methods for the preparation of complex structural units common to polyketide natural products.